Replication factor C3 is a CREB Target Gene that Regulates Cell Cycle Progression through Modulation of Chromatin Loading of PCNA

CREB (cAMP Response Element Binding protein) is a transcription factor overexpressed in normal and neoplastic myelopoiesis and regulates cell cycle progression, although its oncogenic mechanism has not been well characterized. Replication Factor C3 (RFC3) is required for chromatin loading of proliferating cell nuclear antigen (PCNA) which is a sliding clamp platform for recruiting numerous proteins in DNA metabolism. CREB1 expression, which was activated by E2F, was coupled with RFC3 expression during the G1/S progression in the KG-1 acute myeloid leukemia (AML) cell line. There was also a direct correlation between the expression of RFC3 and CREB1 in human AML cell lines as well as in AML cells from patients. CREB interacted directly with the CRE site in RFC3 promoter region. CREB knockdown inhibited primarily G1/S cell cycle transition decreasing expression of RFC3 as well as PCNA loading onto chromatin. Exogenous expression of RFC3 was sufficient to rescue the impaired G1/S progression and PCNA chromatin loading caused by CREB knockdown. These studies suggest that RFC3 may play a role in neoplastic myelopoiesis by promoting the G1/S progression and its expression is regulated by CREB.